7-30595148-C-T

Position:

• chr7-30595148-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002047.4(GARS1):​c.222+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0984 in 1,535,676 control chromosomes in the GnomAD database, including 8,528 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (882 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7646 hom.)
• Consequence: GARS1 NM_002047.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001381
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.00800

Genes affected

GARS1 (HGNC:4162): (glycyl-tRNA synthetase 1) This gene encodes glycyl-tRNA synthetase, one of the aminoacyl-tRNA synthetases that charge tRNAs with their cognate amino acids. The encoded enzyme is an (alpha)2 dimer which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

GARS1-DT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 7-30595148-C-T is Benign according to our data. Variant chr7-30595148-C-T is described in ClinVar as [Benign]. Clinvar id is 137439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30595148-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.222+5C>T		splice_region_variant, intron_variant		ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.60+5C>T		splice_region_variant, intron_variant			NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.222+5C>T		splice_region_variant, intron_variant		1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.222+5C>T		splice_region_variant, intron_variant				ENSP00000502513.1
GARS1	ENST00000675810.1	c.222+5C>T		splice_region_variant, intron_variant				ENSP00000502743.1
GARS1	ENST00000675693.1	c.54+5C>T		splice_region_variant, intron_variant				ENSP00000502174.1
GARS1	ENST00000675051.1	c.22-3648C>T		intron_variant				ENSP00000502296.1
GARS1	ENST00000674815.1	c.-148+196C>T		intron_variant				ENSP00000502799.1
GARS1	ENST00000674851.1	c.-148+5C>T		splice_region_variant, intron_variant				ENSP00000502451.1
GARS1	ENST00000444666.6	n.222+5C>T		splice_region_variant, intron_variant		3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.222+5C>T		splice_region_variant, intron_variant				ENSP00000502408.1
GARS1	ENST00000674643.1	n.222+5C>T		splice_region_variant, intron_variant				ENSP00000501636.1
GARS1	ENST00000674737.1	n.222+5C>T		splice_region_variant, intron_variant				ENSP00000502464.1
GARS1	ENST00000674807.1	n.222+5C>T		splice_region_variant, intron_variant				ENSP00000502814.1
GARS1	ENST00000675529.1	n.222+5C>T		splice_region_variant, intron_variant				ENSP00000501655.1
GARS1	ENST00000675859.1	n.222+5C>T		splice_region_variant, intron_variant				ENSP00000502033.1
GARS1	ENST00000676088.1	n.222+5C>T		splice_region_variant, intron_variant				ENSP00000501884.1
GARS1	ENST00000676140.1	n.222+5C>T		splice_region_variant, intron_variant				ENSP00000502571.1
GARS1	ENST00000676164.1	n.222+5C>T		splice_region_variant, intron_variant				ENSP00000501986.1
GARS1	ENST00000676210.1	n.222+5C>T		splice_region_variant, intron_variant				ENSP00000502373.1
GARS1	ENST00000676259.1	n.222+5C>T		splice_region_variant, intron_variant				ENSP00000501980.1
GARS1	ENST00000676403.1	n.222+5C>T		splice_region_variant, intron_variant				ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15547 AN: 152122 Hom.: 880 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0932

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.0614

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0877

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.113 AC: 15584 AN: 138328 Hom.: 1062 AF XY: 0.117 AC XY: 8729 AN XY: 74722

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0757

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.160

Gnomad SAS exome AF: 0.188

Gnomad FIN exome AF: 0.0619

Gnomad NFE exome AF: 0.0923

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0980 AC: 135578 AN: 1383436 Hom.: 7646 Cov.: 35 AF XY: 0.100 AC XY: 68563 AN XY: 682804

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.0785

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.194

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.0628

Gnomad4 NFE exome AF: 0.0882

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.102 AC: 15558 AN: 152240 Hom.: 882 Cov.: 32 AF XY: 0.103 AC XY: 7671 AN XY: 74442

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.0931

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.178

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.0614

Gnomad4 NFE AF: 0.0876

Gnomad4 OTH AF: 0.132

Alfa AF: 0.0889 Hom.: 714

Bravo AF: 0.106

Asia WGS AF: 0.212 AC: 737 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Distal spinal muscular atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 15, 2016

- -

Charcot-Marie-Tooth disease type 2D Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Neuronopathy, distal hereditary motor, type 5A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2072236; hg19: chr7-30634764; COSMIC: COSV66827729; COSMIC: COSV66827729;